The present invention is directed to ortho-anthranilamide derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.
Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.
In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363; and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology (1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.
Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the xe2x80x9cXa burstxe2x80x9d pathway and by the factor IXa-VIIIa complex (TENase) of the xe2x80x9csustained Xaxe2x80x9d pathway in the coagulation cascade. After vessel injury, the xe2x80x9cXa burstxe2x80x9d pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the xe2x80x9csustained Xaxe2x80x9d pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the xe2x80x9cXa burstxe2x80x9d pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.
The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin III (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique xe2x80x9ctethered ligandxe2x80x9d thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.
Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp. 371-376; and Science (1990), Vol. 248, pp. 593-596).
The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.
European Published Patent Application 0 540 051 (Nagahara et al.) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.
The synthesis of xcex1,xcex1xe2x80x2-bis(amidinobenzylidene)cycloalkanones and xcex1,xcex1xe2x80x2-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.
U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
U.S. Pat. No. 5,691,364 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/21437 (Arnaiz et al.) describes naphthyl-substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.
PCT Published Patent Application WO/97/29067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagularits.
PCT Published Patent Applications WO/96/10022 (Faull et aL), WO97/29104 (Faull et al.), and WO/97/28129 describe aminoheterocyclic compounds which are disclosed as being factor Xa inhibitors, thereby being useful as antithrombotics and anticoagulants.
The above references, published patent applications and U.S. patents are herein incorporated in full by reference.
This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity, i.e., as anti-coagulants.
Accordingly, in one aspect, this invention provides compounds of formula (III): 
wherein
m is 1 to 3;
n is 1 to 5; 
xe2x80x83is an aryl or a heterocyclic ring substituted by R2 and onr or more R1 groups; 
xe2x80x83is an aryl or a heterocyclic ring substituted by one or more R4 groups;
D and E are independently a linker selected from the group consisting of xe2x80x94N(R5)xe2x80x94C(X)xe2x80x94; xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(X)xe2x80x94; xe2x80x94N(R5)xe2x80x94C(X)xe2x80x94R8xe2x80x94; xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(X)xe2x80x94R8xe2x80x94; xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94; xe2x80x94R8xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94; xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94R8xe2x80x94; and xe2x80x94R8xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94R8xe2x80x94(where p is 0 to 2; X is oxygen, sulfur or H2) where D and E can be attached to the B ring having the R1 and R2 substituents by either terminus of the selected linker;
each R1 is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6) or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6);
R2 is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pR9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R19 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R19, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94R8xe2x80x94C(O)OR5 (where p is 0 to 2), or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
R3 is aryl or heterocyclyl both substituted by one or more R14 substituents independently selected from the group consisting of hydrogen, alkyl, halo, formyl, acetyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94N(R10)R11, xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94R8xe2x80x94N⊕(R9)(R16)2, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R15, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94R8xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94R8xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10, xe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94N(R5)R6, heterocyclyl (wherein the heterocyclyl radical is not attached to the rest of the molecule through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), and heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen ring and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
each R4 is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, or xe2x80x94R8xe2x80x94N(R5)R6;
each R5 and R6 is independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R10 and R11 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
R12 is a side chain of an xcex1-amino acid;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6); or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6;
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2; and
each R19 is cycloalkyl, haloalkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)N(R5)R6, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.
In another aspect, this invention provides compounds of formula (I): 
A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1 to 4;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 or xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94 (where p is 0 to 2; Z is oxygen, sulfur or H2; and the nitrogen atom is directly bonded to the phenyl ring having the R1 and R2 substituents);
E is xe2x80x94C(Z)xe2x80x94N(R5)xe2x80x94 or xe2x80x94S(O)pxe2x80x94N(R5)xe2x80x94 (where p is 0 to 2; Z is oxygen, sulfur or H2; and the nitrogen atom can be bonded to the phenyl ring having the R1 and the R2 substituents or to the aromatic ring having the R4 substituent);
each R1 is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94C(O)R5, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
or two adjacent R1""s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring wherein the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl and aralkyl;
R2 is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94OC(O)xe2x80x94R5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R9 (where p is 0 to xe2x80x942), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R19 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R19, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94R8xe2x80x94C(O)OR5 (where p is 0 to 2), or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is hydrogen, alkyl, halo, haloalkyl, xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and
each R14 is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N⊕(R9)(R16)2, xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R15, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6),xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10, xe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94N(R5)R6, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R3 is a radical of the formula (ii): 
xe2x80x83where
v is 1 to 4;
R13 is as defined above for formula (i); and
R14 is as defined above for formula (i);
each R4 is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, or xe2x80x94R8xe2x80x94N(R5)R6;
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR6, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5,xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is I to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
R12 is a side chain of an xcex1-amino acid;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5,xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6); or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6;
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2; and
each R19 is cycloalkyl, haloalkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)N(R5)R6, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof; provided that when A is xe2x95x90CHxe2x80x94, m is 1, n is 1, D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94 (where the nitrogen atom is directly bonded to the phenyl ring having the R1 and R2 substituents), E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen atom is directly bonded to the phenyl ring having the R4 substitutent), R1 is hydrogen and R2 is in the 5-position and is methyl, R4 is in the 4-position and is fluoro, R3 can not be a radical of formula (ii) where v is 1, R14 is hydrogen, and R13 is chloro.
In another aspect, this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, without the proviso, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above, without the proviso.
In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above, without the proviso.
In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of the invention, without the proviso.
Definitions
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
xe2x80x9cAlkylxe2x80x9d refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to a radical of the formula xe2x80x94ORa where Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy, propoxy, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d refers to a radical of the formula xe2x80x94Raxe2x80x94ORa where each Ra is independently an alkyl radical as defined above, e.g., 2-methoxyethyl, methoxymethyl, 3-ethoxypropyl, and the like.
xe2x80x9cAlkylene chainxe2x80x9d refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like.
xe2x80x9cAlkylidene chainxe2x80x9d refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e.g., ethylidene, propylidene, n-butylidene, and the like.
xe2x80x9cAlkylidyne chainxe2x80x9d refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to six carbon atoms, wherein the unsaturation is present only as triple bonds and wherein a triple bond can exist between the first carbon of the chain and the carbon atom of the rest of the molecule to which it is attached, e.g., propylid-2-ynyl, n-butylid-1-ynyl, and the like.
xe2x80x9cAminoxe2x80x9d refers to the xe2x80x94NH2 radical.
xe2x80x9cAminocarbonylxe2x80x9d refers to the xe2x80x94C(O)NH2 radical.
xe2x80x9cArylxe2x80x9d refers to a phenyl or naphthyl radical. Unless otherwise indicated, the term xe2x80x9carylxe2x80x9d refers to phenyl or naphthyl radicals which are optionally substituted by alkyl, halo, xe2x80x94OR5 (where R5 is hydrogen, alkyl, aryl or aralkyl).
xe2x80x9cAralkylxe2x80x9d refers to a radical of the formula xe2x80x94RaRb where Ra is an alkyl radical, as defined above, substituted by Rb, an aryl radical, as defined above, e.g., benzyl.
xe2x80x9cxcex1-Amino Acidsxe2x80x9d refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, omithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, orthotyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A xe2x80x9cside chain of an xcex1-amino acidxe2x80x9d refers to the radical found on the xcex1-carbon of an xcex1-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to a 3- to 7-membered monocyclic cyclic radical which is saturated, and which consists solely of carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
xe2x80x9cDMFxe2x80x9d refers to N,N-dimethylformamide.
xe2x80x9cDMSOxe2x80x9d refers to dimethylsulfoxide.
xe2x80x9cDialkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylamino, diethylamino, (isopropyl)(ethyl)amino, and the like.
xe2x80x9cDialkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(Ra)Ra where each Ra is independently an alkyl radical as defined above, e.g., (dimethylamino)carbonyl, (diethylamino)carbonyl, ((isopropyl)(ethyl)amino)carbonyl, and the like.
xe2x80x9cHaloxe2x80x9d refers to bromo, chloro, iodo or fluoro.
xe2x80x9cHaloalkylxe2x80x9d refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
xe2x80x9cHeterocyclic ringxe2x80x9d refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quatemized; and the ring radical may be partially or fully saturated or aromatic. Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl. For those compounds where two adjacent R1""s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring, the most preferred heterocyclic ring is the dioxolane ring (with the phenyl ring forms a benzodioxole ring).
xe2x80x9cHeterocyclylxe2x80x9d refers to a heterocyclic ring radical as defined above, except that the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
xe2x80x9cHeterocyclylalkylxe2x80x9d refers to a radical of the formula xe2x80x94Raxe2x80x94Rc where Ra is an alkyl radical as defined above and Rc is a heterocyclyl ring radical as defined above, for example, (4-methylpiperazin-1-yl)methyl, (morpholin-4-yl)methyl, 2-(oxazolin-2-yl)ethyl, and the like.
xe2x80x9cN-heterocyclic ringxe2x80x9d refers to those heterocyclic ring radicals defined above which contain at least one nitrogen. The N-heterocyclic ring radical is attached to the main structure through a nitrogen atom in the ring. Examples include, but are not limited to, 4-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, oxazolin-2-yl, and the like. The N-heterocyclic ring may contain up to three additional hetero atoms. Examples include tetrazolyl, triazolyl, thiomorpholinyl, oxazinyl, and the like.
xe2x80x9cHPLCxe2x80x9d refers to high pressure liquid chromatography.
xe2x80x9cMonoalkylaminoxe2x80x9d refers to a radical of the formula xe2x80x94N(H)Ra where Ra is an alkyl radical as defined above, e.g., methylamino, ethylamino, (t-butyl)amino, and the like.
xe2x80x9cMonoalkylaminocarbonylxe2x80x9d refers to a radical of the formula xe2x80x94C(O)N(H)Ra where Ra is an alkyl radical as defined above, e.g., (methylamino)carbonyl, (ethylamino)carbonyl, ((t-butyl)amino)carbonyl, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted arylxe2x80x9d means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d includes both acid and base addition salts.
xe2x80x9cPharmaceutically acceptable acid addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
xe2x80x9cPharmaceutically acceptable base addition saltxe2x80x9d refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity. The amount of a compound of the invention which constitutes a xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity, and includes:
(i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;
(ii) inhibiting the disease-state, i.e., arresting its development, or
(iii) relieving the disease-state, i.e., causing regression of the disease-state.
The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.
For purposes of this invention, in the substituent xe2x80x9cxe2x80x94R8xe2x80x94OR5xe2x80x9d, the xe2x80x9cxe2x80x94OR5xe2x80x9d group may be attached to any carbon in the alkylene, alkylidene or alkylidyne chain.
Some of the compounds of the invention may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclic ring systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.
For purposes of this invention, unless otherwise indicated, the linker moieties between the B ring and the C ring (xe2x80x9cExe2x80x9d) and between the B ring and the R3 moiety (xe2x80x9cDxe2x80x9d) may be independently attached to the B ring on either end of the linker.
For purposes of this invention, the quaternary salts represented by xe2x80x9cxe2x80x94N⊕(R9)(R16)2xe2x80x9d include aromatic rings wherein both R16""s together with the nitrogen to which they are attached form an aromatic ring and it is understood that R9 is not present.
The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art.
The nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as derivatives of benzamide. For example, a compound of the invention selected from formula (I) where A is xe2x80x94Nxe2x80x94; m is 1; n is 1; E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 where the nitrogen atom is bonded to pyridine ring; D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94 where the nitrogen atom is bonded to the phenyl ring; R1 is in the 5-position and is chloro; R2 is in the 3-position and is xe2x80x94N(R10)R11 where R10 and R11 together with nitrogen to which they are attached form a morpholin-4-yl ring; R4 is in the 5-position and is chloro; and R3 is selected from formula (i): 
where R13 is chloro, r is 1 and R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R is hydrogen, R10 is methyl and R11 is 1-methylpiperidin-4-yl; i.e., a compound of the following formula (with position numbers indicated): 
is named herein as N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.
For purposes of this specification, parenthesis are used to denote substituents of a main atom. For example, xe2x80x94C(R7)Hxe2x80x94N(R10)R11 refers to the radical: 
Carbonyl and thiocarbonyl groups are indicated as xe2x80x94C(O)xe2x80x94 and xe2x80x94C(S)xe2x80x94, respectively, and optionally substituted imino radicals are indicated as xe2x95x90N(R17).
Substituents having repeating sections are indicated by brackets (or parenthesis) and the repeating integer. For example, the substituent xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94(R8xe2x80x94O)txe2x80x94R5 where t is 3 refers to the the substituent xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94R8xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94R5.
Utility and Administration
A. Utility
The compounds of the invention are inhibitors of the serine protease, factor Xa, and are therefore useful in disease-states characterized by thrombotic activity based on factor Xa""s role in the coagulation cascade (see Background of the Invention above). Primarily, the compounds of the invention are useful as anti-coagulants. A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumarin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.
In addition, the compounds of the invention are useful as in vitro diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.
B. Testing
The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).
Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the Ki in the primary enzyme assay with the Ki for free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the Ki with the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.
For further information on assays to demonstrate the activity of the compounds of the invention, see R. Loftenberg et al., Methods in Enzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et at, Thrombosis Research (1980), Vol. 19, pp. 579-588.
C. General Administration
Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharin, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
Preferred Embodiments
Of the compounds disclosed in the Summary of the Invention, certain compounds are preferred.
The most preferred compounds of the invention are those compounds selected from formula (III) having the formula (I): 
A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1 to 4;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 or xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94 (where p is 0 to 2; Z is oxygen, sulfur or H2; and the nitrogen atom is directly bonded to the phenyl ring having the R1 and R2 substituents);
E is xe2x80x94C(Z)xe2x80x94N(R5)xe2x80x94 or xe2x80x94S(O)pxe2x80x94N(R5)xe2x80x94 (where p is 0 to 2; Z is oxygen, sulfur or H2; and the nitrogen atom can be bonded to the phenyl ring having the R1 and the R2 substituents or to the aromatic ring having the R4 substituent);
each R1 is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94C(O)R5, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
or two adjacent R1""s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring wherein the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl and aralkyl;
R is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94OC(O)xe2x80x94R5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R9 (where p is0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R19 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R19, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94R8xe2x80x94C(O)OR5 (where p is 0 to 2), or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is hydrogen, alkyl, halo, haloalkyl, xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and
each R14 is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N⊕(R9)(R16)2, xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R15, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10, xe2x80x94C(NR17)xe2x80x94N(R5)R6,xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94N(R5)R6, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R3 is a radical of the formula (ii): 
xe2x80x83where
v is 1 to 4;
R13 is as defined above for formula (i); and
R14 is as defined above for formula (i);
each R4 is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, or xe2x80x94R8xe2x80x94N(R5)R6;
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which theye attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
R12 is a side chain of an xcex1-amino acid;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6); or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6); or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6;
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2; and
each R19 is cycloalkyl, haloalkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)N(R5)R6, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6).
Of these compounds, a preferred group of compounds are those compounds wherein:
A is xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1 to 4;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 (where Z is oxygen, sulfur or H2, and R5 is hydrogen or alkyl);
E is xe2x80x94C(Z)xe2x80x94N(R5)xe2x80x94 (where Z is oxygen, sulfur or H2, R5 is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);
R1 is halo or haloalkyl;
R2 is xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1) or xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where:
each R5 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain;
R9 is alkyl; and
R10 and R11 are each independently hydrogen, alkyl, or xe2x80x94R8xe2x80x94Oxe2x80x94R5 (where R8 is a straight or branched alkylene chain and R5 is hydrogen or alkyl);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen; and
R10 and R11 together with the nitrogen to which they are attached form piperazinyl optionally substituted by one or more substituents selected from the group consisting of alkyl and xe2x80x94C(O)R5; and
R4 is hydrogen or halo.
Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R1 is halo in the 5-position;
R2 is xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1) or xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where:
each R is independently hydrogen, methyl or ethyl;
each R8 is independently a methylene, ethylene or propylene chain;
R9 is methyl or ethyl; and
R10 and R11 are each independently hydrogen, methyl, ethyl, or xe2x80x94R8xe2x80x94Oxe2x80x94R5 (where R8 is ethylene and R5 is hydrogen, methyl or ethyl); or
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is chloro; and
R14 is in the 4-position and is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen; and
R10 and R11 together with the nitrogen to which they are attached form piperazinyl optionally substituted by methyl or ethyl; and
R4 is hydrogen, bromo or chloro in the 5-position.
Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:
R1 is chloro;
R2 is xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5 or xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 or 2) where:
each R5 is independently hydrogen, methyl or ethyl;
each R8 is independently a methylene, ethylene or propylene chain; and
R9 is methyl or ethyl.
Of this class of compounds, more preferred compounds are those compounds selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(methylthio)methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide, and
N-(5-chloropydidin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide.
Of this subgroup of compounds, another preferred class of compounds are those compounds wherein:
R1 is chloro; and
R2 is xe2x80x94N(R10)R11 or xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where:
R8 is a methylene, ethylene or propylene chain; and
R10 and R11 are each independently hydrogen, methyl, ethyl, or xe2x80x94R8xe2x80x94Oxe2x80x94R5 (where R8 is ethylene and R5 is hydrogen, methyl or ethyl).
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)propoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide.
Of this subgroup of compounds, another preferred class of compounds are those compounds wherein:
R1 is chloro;
R2 is xe2x80x94N(R10)R11 or xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where:
R8 is methylene, ethylene or propylene; and
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl and is selected from the group consisting of morpholinyl, piperazinyl, pyrrolidinyl or imidazolyl.
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-morpholinylpropoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1 to 4;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 (where Z is oxygen, sulfur or H2, and R5is hydrogen or alkyl);
E is xe2x80x94C(Z)xe2x80x94N(R5)xe2x80x94 (where Z is oxygen, sulfur or H2, R5 is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);
R1 is halo or haloalkyl;
R2 is hydrogen, haloalkyl, or xe2x80x94OR5 where R5 is hydrogen or alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
each R14 is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N⊕(R9)(R16)2, xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R15, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10, xe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94N(R5)R6, hetrocyclyl (wherein the hetrocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6); where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where
each R5 is hydrogen, alkyl, aryl or aralkyl; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR , or xe2x80x94NO2;
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R5xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain; or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
and R4 is hydrogen or halo.
Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R is hydrogen, haloalkyl, or xe2x80x94OR5 where R5 is hydrogen or alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where
each R5 is hydrogen, alkyl, aryl or aralkyl; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2;
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6 where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
and R4 is in the 5-position.
Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R8), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6) where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where
each R5 is independently hydrogen, alkyl, aryl or aralkyl; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2.
Of this class of compounds, a preferred subclass of compounds are those compounds wherein:
R10 is hydrogen, alkyl, or xe2x80x94R8xe2x80x94OR5; and
R11 is hydrogen, alkyl or xe2x80x94R8xe2x80x94OR5;
where each R8 is independently a straight or branched alkylene chain, and each R5 is hydrogen or alkyl.
Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2,Nxe2x80x2-di(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,2-dimethyl-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-ethoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1-methylethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(ethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-(diethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of this class of compounds, another preferred subclass of compounds are those compounds wherein:
R10 is hydrogen, alkyl, or xe2x80x94R8xe2x80x94N(R5)R6, and
R11 is xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2) or xe2x80x94R8xe2x80x94N(R5)R6 where:
R5 and R6 are independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain; and
R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR , xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6) where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this subclass of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(methyl)sulfonyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((3,5-dimethylisoxazol-4-yl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((2-(4-hydroxypiperidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(4-(dimethylamino)but-3-yn-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of this class of compounds, another preferred subclass of compound are those compounds wherein:
R10 is hydrogen, alkyl or xe2x80x94R8xe2x80x94OR5; and
R11 is formyl, cyano, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, or xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, where:
each R5 is hydrogen or alkyl;
R8 is a straight or branched alkylene chain;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6) where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2.
Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-carboxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(morpholin-4-yl)ethyl)thioureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(((4-hydroxypiperidin-1-yl)methyl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(acetoxy)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x3-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(((2-hydroxyphenyl)carbonyl)oxy)ethyl)ureido)-methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-((fluoromethylcarbonyl)amino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((2-aminoethoxy)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((methylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-((phenylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-nitro-1-(methylamino)ethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((2-dimethylphosphoramidoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the class of compounds, another preferred subclass of compounds are those compounds wherein:
R10 is hydrogen, alkyl, haloalkyl, or xe2x80x94R8xe2x80x94OR5;
R11 is cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6) where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this subclass of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(pyridin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4-(oxo)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(pyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropynidin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(t-butyl)-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((thiazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-methoxyethyl)-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chiorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(5-methyloxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(tetrazol-5-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(4-methyloxazolin-2-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(pyrazol-3-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2,2,2-trifluoroethyl)-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1,2,4-triazol4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-amino-6-methylpyrimidin-4-yl)amino)methyl)-3chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-(imidazol4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropynidin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3,4,5,6-tetrahydropyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-chloropyrimidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chlorbpyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-((imidazol-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorpbenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(4-(methylamino)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((3-((methylthio)methyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1,3,2-dioxaphospholan-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the subgroup of compounds, another preferred class of compounds are those compounds wherein:
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6 where
R5 and R5 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this class of compounds, a preferred subclass of compounds are those compounds wherein the N-heterocylic rng is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, and nitro.
Of this subclass of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dihydropyrazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((morpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((pyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((hydantoin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(pyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(5-bromopyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,4-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,5-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dichloroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(chloromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((2-(fluoromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by one or more substituents selected from the group consisting of alkyl, nitro, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl.
Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((4-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-(hydroxymethyl)imidazol-1-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxymethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-formylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(Nxe2x80x2-amino-Nxe2x80x2-methylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-hydroxypiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanomethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x95x90N(R17), xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94(R8xe2x80x94O)txe2x80x94R5, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, or xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6 where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this subclass of compounds, preferred compounds are those wherein the N-heterocylic ring is substituted by xe2x95x90N(R17) and is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, and xe2x80x94(R8xe2x80x94O)txe2x80x94R5, where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6 where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of these compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-ethylimino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(R)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-(methoxethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((trans-4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((3-methyl-2-imino-2,3-dihydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1,2-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-(hydroxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrothiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-oxoimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((tetrahydro-2-imino-2H-pyrimidin-1-ylpyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxycarbonylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanoimino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-3-((phenylamino)carbonyl)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((cis4,5-dimethoxy-2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-4-imino-1,4-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-((2-hydroxyethyl)imino)tetrahydroimidazol-l-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-imino-1(4H)-pyridinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1(2H)-pyridin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylimino)pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((2-(((aminocarbonyl)methyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by xe2x80x94N(R5)R6 and optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x80x94N(R5)R6, xe2x80x94OR5, and xe2x80x94C(O)N(R5)R6, where R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl.
Of this subclass of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-aminotetrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((3-amino-1,2,4-triazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((3,5-diamino-4H-1,2,4-triazol-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-amino-5-(aminocarbonyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-2-oxo-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2,4-diamino-6-hydroxypyrimidin-5-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(1-methylethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-2-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the group of compounds described above, another preferred subgroup of compounds are those compounds wherein:
each R14 is independently alkyl, xe2x80x94R8xe2x80x94CN, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N⊕(R9)(R16)2, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R15, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8-[CH(OH)]t-CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)H-xe2x80x94Oxe2x80x94N(R5)R6, or heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R5xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where
each R5 is hydrogen, alkyl, aryl or aralkyl; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2;
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(C)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR51, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)R5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain; or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this subgroup of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((N-methyl-Nxe2x80x2-(2-(hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((methylsulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)sulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(2-methylaminoethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(hydroxy)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((imidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2[((4-((imidazolin-2-yl)thio)methyl)3-chlorothiopen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((5-hydroxymethyl-1-methylimidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the group of comounds described above, another preferred subgroup of compounds are those compounds wherein:
each R14 is independently xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10, or xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94N(R5)R6, where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7is independently hydrogen or alkyl;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R15 is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where
each R5 is hydrogen, alkyl, aryl or aralkyl; and
R18 is hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94C(O)OR5, or xe2x80x94NO2;
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(C))OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), where
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R9 is independently alkyl, aryl or aralkyl;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain;
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, where
R5 and R6 are independently each hydrogen, alkyl, aryl or aralkyl, and
each R8 is independently a straight or branched alkylene, alkylidene or alkylidyne chain.
Of this subgroup of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-(((amidino)(methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1-iminoethyl)-Nxe2x80x2-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2,Nxe2x80x3-dimethyl-Nxe2x80x2xe2x80x3-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2-methyl-Nxe2x80x3-hydroxyguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2-methyl-Nxe2x80x3-(2-aminoethyl)-Nxe2x80x2xe2x80x3-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2-methyl-Nxe2x80x3-aminoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2,Nxe2x80x3-dimethyl-Nxe2x80x2xe2x80x3-(aminocarbonyl)guanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(imino(phenyl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1-imino-2-(aminocarbonyl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1-imino4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(imino(pyridin4-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(imino(thiophen-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(imino(pyrazin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(cyclopropyl(imino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(3-cyano-1-iminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxylmino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R2 is xe2x80x94N(R10)R11 where:
R10 and R11 are each independently hydrogen, alkyl or xe2x80x94R8xe2x80x94Oxe2x80x94R5 where R8 is an alkylene chain, and R5 is hydrogen or alkyl; or
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and xe2x80x94C(O)OR5 where R5 is hydrogen or alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 or xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 3) where:
each R5 is independently hydrogen or alkyl;
R7 is hydrogen;
R8 is a straight or branched alkylene chain;
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), where:
each R5 and R6 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, and xe2x80x94N(R5)R6; where
each R5 and R6 is independently hydrogen or alkyl;
R8 is a straight or branched alkylene chain; and
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8C(O)xe2x80x94N(R5)R6;
and R4 is in the 5-position and is hydrogen or halo.
Of this group of compound, a preferred subgroup of compounds are those compounds wherein:
R2 is xe2x80x94N(R10)R11 where:
R10 and R11 are each independently hydrogen, alkyl or xe2x80x94R8xe2x80x94Oxe2x80x94R5 where R8 is an alkylene chain, and R15 is hydrogen or alkyl.
Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen;
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5); where:
each R5 and R6 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, and xe2x80x94N(R5)R6; where:
each R5 is hydrogen or alkyl;
R8 is straight or branched alkylene chain; and
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6.
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((N-methyl-Nxe2x80x2-(1-methylpiperidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(di(2-methoxyethyl)amino)-5-chlorobenzamide.
Of this group of compounds, another preferred subgroup of compounds are those compounds wherein:
R is xe2x80x94N(R10)R11 where:
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and xe2x80x94C(O)OR5 where R5 is hydrogen or alkyl.
Of this subgroup of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyeidin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-methoxyethyl)amino)methyl)-3-chlorothiophen-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methylsulfonylxe2x80x94Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x3-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-(1-methylethyl)-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-yl)carbonyl)amino]-3-(4-(carboxy)piperidin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(4trifluoromethyl-5-carboxypyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R2 is xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 3) or xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R19 where R5 is hydrogen or alkyl, each R8 is independently a straight or branched alkylene chain, and R19 is heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, or haloalkyl);
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen;
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclal (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5); where:
each R5 and R6 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, and xe2x80x94N(R5)R6; where
each R5 is hydrogen or alkyl;
R8 is straight or branched alkylene chain; and
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6; and
R4 is in the 5-position and is hydrogen or halo.
Of this group of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;
N-(5-chloropynidin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3-dihydroxypropyl)amino) methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-ethyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyridin-3-yloxy)propoxy)-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R is xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where:
R8 is a straight or branched alkylene chain; and
R10 and R11 are each independently hydrogen, alkyl or xe2x80x94R8xe2x80x94Oxe2x80x94R where R8 is an alkylene chain, and R5 is hydrogen or alkyl; or
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and xe2x80x94C(O)OR5 where R5 is hydrogen or alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen;
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), where:
each R5 and R6 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5); and
R4 is in the 5-position and is hydrogen or halo.
Of this group of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-N-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(4-ethylpiperazin-1-yl)propoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-aminoethoxy)-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1;
n is 1;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94 (where the nitrogen is bonded to the 2-position of the pyridinyl ring);
R2 is xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, or xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5 where
each R5 is hydrogen or alkyl;
R8 is a straight or branched alkylene chain; and
R10 and R11 are each independently hydrogen, alkyl or xe2x80x94R8xe2x80x94Oxe2x80x94R5 where R8 is an alkylene chain, and R5 is hydrogen or alkyl; or
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and xe2x80x94C(O)OR5 where R5 is hydrogen or alkyl;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 or xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11 where:
R5 is hydrogen or alkyl;
R7 is hydrogen;
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S) greater than NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5); where:
each R5 and R6 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5); and
R4 is in the 5-position and is hydrogen or halo.
Of this group of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(imidazol-1-yl)propoxy)-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-methoxypropoxy)-5-chlorobenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 (where Z is oxygen and R5 is hydrogen or alkyl);
E is xe2x80x94C(Z)xe2x80x94N(R5)xe2x80x94 (where Z is oxygen, R5 is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);
each R1 is independently hydrogen, halo or xe2x80x94OR5;
or two adjacent R1""s together with the carbons to which they are attached form a dioxole ring fused to the phenyl ring wherein the dioxole ring is optionally substituted by alkyl;
R is hydrogen;
R3 is a radical of the formula (i): 
xe2x80x83where
r is 1;
R13 is halo; and
R is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen; and
R10 and R11 are each independently hydrogen, alkyl, formyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, xe2x80x94OR5, and xe2x80x94C(O)OR5); where:
each R5 and R6 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by xe2x80x94R8xe2x80x94OR5), or heterocyclylalkyl (optionally substituted by xe2x80x94OR5); and
R4 is in the 5-position and is hydrogen or halo.
Of this group of compounds, preferred compounds are selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3,4,5-trimethoxybenzamide;
5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;
5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole; and
5-(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((Nxe2x80x2-(2-methoxyethyl)-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x80x94CHxe2x80x94;
m is 1;
n is 1;
D is xe2x80x94N(R5)xe2x80x94C(Z)xe2x80x94 (where Z is oxygen and R5 is hydrogen or alkyl);
E is xe2x80x94C(Z)xe2x80x94N(R )xe2x80x94 (where Z is oxygen, R5 is hydrogen or alkyl, and the nitrogen is attached to the phenyl ring having the R4 substituent);
R1 is alkyl or halo;
R2 is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94O)xe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5; Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94R8xe2x80x94C(O)OR5 (where p is 0 to 2), xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is hydrogen, alkyl, halo, haloalkyl, xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and
each R14 is independently hydrogen, alkyl, halo, formyl, acetyl, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)tR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)tR5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, or xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10;
R4 is halo;
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
R7is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene or alkylidene chain;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, aryl, aralkyl, formyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
R12 is a side chain of an xcex1-amino acid;
each R15 is independently alkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6).
Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94;
R1 is halo;
R2 is hydrogen, xe2x80x94OR5, xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5 or xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5 where:
each R5 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain;
R9 is alkyl;
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms;
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1;
R13 is halo; and
R14 is in the 4-position and is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen or alkyl; and
R10 and R11 are each independently hydrogen, alkyl, xe2x80x94R8xe2x80x94OR5 or heterocyclyl;
or R10 and R11 together with the nitrogen to which they are attached form a piperazine ring optionally substituted by alkyl; and
R4 is chloro.
Of this subgroup of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-fluorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((acetoxy)ethoxy)-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(morpholin-4-yl)ethoxy)-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((methylthio)methoxy)-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((N-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide; and
N-(4-chlorophenyl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of the group of compounds described above, another preferred subgroup of compounds are those compounds wherein:
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94;
R1 is methyl or chloro;
R2 is hydrogen or xe2x80x94OR5;
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is alkyl, halo, OR5 (where R5 is alkyl) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by alkyl); and
each R14 is independently hydrogen, alkyl, halo, formyl, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, or xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6);
R4is halo;
R5 and R6 are each independently hydrogen or alkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain;
R9 is alkyl;
R10 and R11 are each independently hydrogen, alkyl, aryl, aralkyl, formyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R5, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring .containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, C(O)R5, and xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
R15 is alkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, xe2x80x94OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), or
both R16""S together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6).
Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is halo, alkyl or 4-methylpiperazin-1-yl, and
each R14 is independently hydrogen or xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen or alkyl;
R10 and R11 are each independently hydrogen, alkyl, aryl, aralkyl, formyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94(C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR51, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6) where:
each R5 and R6 are independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain; and
each R15 is alkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6).
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((5-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(N-methyl-N(2-hydroxyethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(Nxe2x80x2-methyl-Nxe2x80x2-(ethoxycarbonylmethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(Nxe2x80x2-methyl-Nxe2x80x2-(carboxymethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(Nxe2x80x2,Nxe2x80x2-di(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((Nxe2x80x2-(3-dimethylaminophenyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4,5-di((n-propyl)aminomethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((Nxe2x80x2-methyl-Nxe2x80x2-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(ethoxycarbonyl methyl) amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-(3-(imidazol-1-yl)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(3-(dimethylamino)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-(2-methylpropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(1-methylpiperidin-4-yl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-hydroxyamino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-diethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-(2-hydroxyethy)-Nxe2x80x2-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.
Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is halo or alkyl, and
each R14 is independently hydrogen, alkyl or xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where:
R7 is hydrogen or alkyl; and
R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)R5, and xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6) where
each R5 is hydrogen or alkyl; and
R8 is a straight or branched alkylene chain.
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(carboxymethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((5-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(ethoxycarbonylmethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(morpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(((2-(2-methoxyethoxy)ethoxy)methyl)carbonyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(1,1,4-tri(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-methyl-4-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((4H-1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((pyrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,34triazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((4-ethylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((4-oxomorpholin-4-yl) methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((4-acetylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and
N-(4-chlorophenyl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Of this subgroup of compounds described above, another preferred class of compounds are those compounds wherein:
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is halo or alkyl, and
each R14 is independently xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 where:
p is 0 to 2;
R7 is hydrogen or alkyl; and
R15 is alkyl, xe2x80x94R8xe2x80x94N(R5)R6 or xe2x80x94R8xe2x80x94C(O)OR5 where:
R5 and R6 are each independently hydrogen or alkyl; and
each R8 is independently a straight or branched alkylene chain.
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((3-chloro-5-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((carboxymethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-5 yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and
N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.
Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is halo or alkyl, and
each R14 is independently formyl, xe2x80x94N(R10)R11, xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94OR5 or xe2x80x94C(O)N(R5)R6 where:
R5 and R6 are each independently hydrogen or alkyl;
R7 is hydrogen or alkyl; and
R10 and R11 are independently hydrogen or alkyl.
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((3-chloro-5-carboxythiophen-2-yl)carbonyl)amino]-5-chiorobenzamide; and
N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.
Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:
R3 is a radical of formula (i): 
xe2x80x83where:
r is 1 or 2;
R13 is alkyl, halo or xe2x80x94OR5 (where R5 is alkyl), and
each R14 is independently hydrogen, halo, xe2x80x94C(R7)Hxe2x80x94N61 (R9)(R16)2, xe2x80x94S(O)pxe2x80x94R15, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)tR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, or xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8-[CH(OH)]tCH2xe2x80x94OR5 (where t is 6) where t is 1 to 6) where:
R5 and R6 are independently hydrogen or alkyl;
R7 is hydrogen or alkyl;
each R8 is independently a straight or branched alkylene chain;
R10 and R11 are independently hydrogen, alkyl or xe2x80x94Rxe2x80x94OR5 where R is a straight or branched alkylene chain and R5 is hydrogen or alkyl; and
R15 is alkyl or xe2x80x94N(R5)R6; and
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6).
Of this class of compounds, preferred compounds are selected from the group consisting of:
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2,Nxe2x80x2-dimethyl-Nxe2x80x2-(2-hydroxyethyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((((2-hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-methoxyethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((2-methoxyethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-((N,Nxe2x80x2-dimethyl-Nxe2x80x2-(3-hydroxypropyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3-dihydroxypropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3,4,5,6-pentahydroxyhexyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-(hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-(methylsulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-bromothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-4-((1-methylethyl)sulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((4-(methylamino)sulfonethyl3-methylthiophen-2-yl)carbonyl)amino]-5-methylbenzamide; and
N-(4-chlorophenyl)-2-[((3-methoxythiophen-2-yl)carbonyl)amino]-5-methylbenzamide.
Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:
A is xe2x80x94CHxe2x80x94 or xe2x95x90Nxe2x80x94;
m is 1 to 3;
n is 1 to 4;
D is xe2x80x94N(H)xe2x80x94C(O)xe2x80x94 or xe2x80x94N(H)xe2x80x94CH2xe2x80x94;
E is xe2x80x94C(O)xe2x80x94N(H)xe2x80x94; (where the nitrogen atom is bonded to the aromatic ring containing the R4 substituent);
each R1 is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where is p 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94C(O)R5, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5;
R2 is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, xe2x80x94OR5, xe2x80x94S(O)pR9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94OC(O)xe2x80x94R5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, C(R5∂)Hxe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5; xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8C(O)OR5, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5) R6 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94R8xe2x80x94(O)OR5 (where p is 0 to 2), or xe2x80x94N(R5)xe2x80x94CH(R12, xe2x80x94C(O)OR5;
R3 is a radical of formula (ii): 
xe2x80x83where
v is 1 to 4;
R13 is hydrogen, alkyl, halo, haloalkyl, xe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and
each R14 is independently hydrogen, alkyl, halo, formyl, acetyl, xe2x80x94N(R10))R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N⊕(R9)(R16)2, xe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R5 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6(where p is 0 to 2), xe2x80x94C(O)N(R5)R6, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)tR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94R8[CH(OH)]txe2x80x94CH2xe2x80x94OR5 (where t is 1 to 6), xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94S(O)2xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R10)R11, or xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10;
each R4 is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, or xe2x80x94R8xe2x80x94N(R5)R6;
R5 and R6 are each independently hydrogen, alkyl, aryl or aralkyl;
each R7 is independently hydrogen or alkyl;
each R8 is independently a straight or branched alkylene or alkylidene chain;
each R9 is independently alkyl, aryl or aralkyl;
R10 and R11 are each independently hydrogen, alkyl, aryl, aralkyl, formyl, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6);
or R10 and R11 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6);
R12 is a side chain of an xcex1-amino acid;
R15 is alkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94N(R5)R6, xe2x80x94R5xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclycyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6);
or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, OR5, xe2x80x94C(O)OR5, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and
each R16 is independently alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents; selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R )R6), or
both R16""s together with the nitrogen to which they are attached (and wherein the R9 substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)R6,xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)tR5 (where t is 1 to 6), and xe2x80x94(R8xe2x80x94O) R5 (where t is 1 to 6); and
each R17 is independently hydrogen, alkyl, aryl, aralkyl, cyano, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6, or xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6.
Of this group of compounds, preferred compounds are selected from the group consisting of:
N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(pyridin-3-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(pyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-methoxyphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(3-fluorophenyl)-2-[((3-ctilorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(5-chloropyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(3-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(3-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chloro-2-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-cyanophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-fluorophenyl)-2-[((benzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-fluorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-methoxybenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;
N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;
N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methoxybenzamide;
N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-phenyl-2-[((3-chlorobenzol[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;
N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(pyrrolidin-1-yl)methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-(trifluoromethyl)benzamide;
N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(dimethylamino)methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(4-methylpiperazin-1-yl) benzamide;
N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(amino)methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxybenzamide;
N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-dimethoxybenzamide;
N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-dihydroxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-fluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-chlorobenzamide;
N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;
N-phenyl-2-[((3-chlorobenzo [b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-fluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-6-fluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4,5-hydroxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dimethoxybenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-aminobenzamide;
N-(4-chlorophenyl)-2-[((3-chliorobenzo[b]thien-2-yl)carbonyl)amino]4-methyl-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methyl-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluoro-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;
N-(4-chlorophenyl) 2-[((3-chlorobenzol[b]thien-2-yl)carbonyl)amino]4,5-difluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(Nxe2x80x2-methyl-Nxe2x80x2-(3-(dimethylamino)propylamino-5-fluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]4-(4-methylpiperazin-1-yl)-5-fluorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-((3-(4-methylpiperazin-1-yl)propyl)amino)-5-fltorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-6-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chiloro-6-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-6-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-6-(4-(carboxymethyl)piperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chloro-6-((methoxycarbonyl)methylthio)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(Nxe2x80x2-methyl-Nxe2x80x2-(ethoxycarbonylmethylamino)benzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(Nxe2x80x2-methyl-Nxe2x80x2-(2-(dimethylamino)ethyl)amino)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(Nxe2x80x2-methyl-Nxe2x80x2-(ethoxycarbonyl)methylamino)benzamide;
N-phenyl-2-[((3-chlorobenzo[b ]-thien-2-yl)carbonyl)amino]-5-hydyroxy-4-((1,1-dimethylethyl)carbonyl)oxybenzamide; and
Nxe2x80x2-(4-chlorophenyl)-2-((3-methylbenzo[b]thien-2yl)methyl)amino-5-benzamide.
Of the compounds disclosed above, the following compounds are the most preferred compounds of the invention:
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x3-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide
N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,
N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;
N-(5-chloropyridin-2-yl)-2-[((4-((Nxe2x80x2-methyl-Nxe2x80x2-(pyridin4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and
N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.
Preparation of Compounds of The Invention
It is understood that in the following description, combinations of substituents and/or variables on the depicted formulae are permissible only if such combinations result in stable compounds.
For purposes of illustration only and unless otherwise indicated, the following Reaction Schemes are directed to the preparation of the compounds of the invention as set forth above in the Summary of the Invention as compounds of formula (I). In particular, for purposes of illustration only and unless otherwise indicated, the compounds prepared in the following Reaction Schemes are compounds of formula (I) wherein D is xe2x80x94N(R5)xe2x80x94C(O)xe2x80x94(where the nitrogen is bonded to the phenyl ring having the R1 and R2 substituents), and E is xe2x80x94C(O)xe2x80x94N(R5)xe2x80x94 (where the nitrogen is bonded at the 2-position of the pyridinyl (if A is xe2x95x90Nxe2x80x94) or to the phenyl (if A is xe2x95x90CHxe2x80x94) having the R4 substituent) and R3 is a radical of the formula (i): 
where each R13 and each R14 are as described in each following Reaction Scheme. It is understood that the other compounds of the invention may be prepared by similar methods as described herein.
A. Preparation of Compounds of Formula (Ia)
Compounds of formula (Ia) are compounds of the invention wherein R13 is chloro and the R14 substituent is in the 4-position of the thienyl radical. These compounds are prepared as described below in Reaction Scheme 1 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94, each R1a is independently hydrogen, alkyl, aryl, aralkyl, halo, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)R6; R2a is hydrogen, alkyl, aryl, aralkyl, halo, cyano, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)N(R5)R61, xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(R7)Hxe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94OR5, xe2x80x94C(R7)Hxe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(R7)Hxe2x80x94N(R5)R6, xe2x80x94C(R7)Hxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94(R8xe2x80x94O)tR19 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R5, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)R19, xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94S(O)pxe2x80x94R8N(R5)R6 (where p is 0 to 2), or xe2x80x94S(O)pxe2x80x94R8xe2x80x94C(O)OR5 (where p is 0 to 2); each R4 is independently hydrogen, alkyl, halo, cyano, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, or xe2x80x94R8xe2x80x94N(R5)R6; each R5 and R6 is as described above in the Summary of the Invention for compounds of formula (I); R5ais hydrogen; R7 is hydrogen or alkyl; each R8 and R9 are as described above in the Summary of the Invention for compounds of formula (I); each R10 and R11 is independently hydrogen, alkyl, aryl, aralkyl, formyl, cyano, xe2x80x94R8xe2x80x94CN, xe2x80x94OR5, xe2x80x94R8, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)NH2, xe2x80x94R8xe2x80x94C(O)NH2, xe2x80x94C(S)NH2, xe2x80x94C(O)xe2x80x94Sxe2x80x94R5xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R15, xe2x80x94C(S)xe2x80x94N(R5)R15, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)H, xe2x80x94R8xe2x80x94N(R5)xe2x80x94C(O)R15, xe2x80x94C(O)Oxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(N(R5)R6)xe2x95x90C(R18)R10, xe2x80x94R8xe2x80x94N(R5)xe2x80x94P(O)(OR5)2, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and xe2x80x94OR5), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, xe2x80x94OR5, xe2x80x94R8xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94N(R5)R6 and xe2x80x94C(O)N(R5)R6); or R10 and R11 together with nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17), xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94C(O)N(R5)R6, xe2x80x94R8xe2x80x94C(O)N(R5)R6, xe2x80x94N(R5)xe2x80x94N(R5)R6, xe2x80x94C(O)R5, xe2x80x94C(O)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6, and xe2x80x94C(O)N(R5)R6); R14a is cyano, xe2x80x94N(R10)R11, xe2x80x94N⊕(R9)(R16)2, xe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94Sxe2x80x94R15, xe2x80x94Sxe2x80x94R8xe2x80x94C(O)OR51, xe2x80x94Sxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94N(R5)xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94N(R5)xe2x80x94R8xe2x80x94[CH(OH)]txe2x80x94CH2xe2x80x94OR15 (where t is 1 to 6), xe2x80x94Sxe2x80x94R8xe2x80x94OR15; or R14a is heterocyclycyl wherein the heterocyclic ring is optionally substituted by alkyl, aryl, aralkyl, oxo, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6; where each R15 and R16 are as described above in the Summary of the Invention for compounds of formula (I) except that neither can be or contain haloalkyl; R17 is as described in the Summary of the Invention for compounds of formula (I); and X is chloro or bromo: 
Compounds of formula (A), formula (C), and formula (H) are commercially available, for example, from Aldrich Co. Compounds of formula (F) are commercially available or may be prepared according to methods described herein.
In general, compounds of formula (Ia) are prepared by first reacting a compound of formula (A) in an aprotic solvent, for example, methylene chloride, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., with a halogenating agent, for example, oxalyl chloride. The reaction mixture is allowed to warm to ambient temperature and stirred for about 8 to 20 hours, preferably for about 16 hours, to produce a compound of formula (B), which is isolated from the reaction mixture by standard techniques (such as removal of solvents).
The compound of formula (B) in an aprotic solvent, for example, methylene chloride, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., is then treated with a compound of formula (C) in the presence of a base, for example, triethylamine. The reaction mixture is then stirred for about 20 to 30 minutes, preferably for about 20 minutes, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., then warmed to ambient temperature, and stirred for about 1 to about 20 hours, preferably for about 16 hours. The compound of formula (D) is then isolated from the reaction mixture by standard isolation techniques, such as evaporation of solvents, extraction and concentration.
The compound of formula (D) is then reduced by treatment with a reducing agent, such as tin(II) chloride under standard reducing conditions to produce a compound of formula (E), which is isolated from the reaction mixture by standard techniques.
The compound of formula (E) in an aprotic solvent, for example, methylene chloride, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., is then treated with a compound of formula (F) in the presence of a base, for example, pyridine. The compound of formula (G) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and trituration with water.
The compound of formula (G) in an aprotic solvent, such as DMF, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., is then treated with a compound of formula (H). The reaction mixture is stirred for about 20 minutes to an hour, preferably for about 30 minutes, and then allowed to warm to ambient temperature. After stirring for about 6 to about 20 hours, preferably for about 7 hours, the compound of formula (Ia) is isolated from the reaction mixture by standard isolation techniques, such as filtration and purification by flash chromatography.
The compound of formula (H) may be present as an acid salt, wherein the corresponding free base is formed in situ by the addition of a base to the reaction mixture, or is treated with a base prior to the reaction with the compounds of formula (G) to form the free base.
Any unprotected amino substituent must be protected prior to Step 4 to avoid acylation. Any carboxy substituent must also be esterified prior to Step 1. The resulting compounds may be deprotected when needed by appropriate methods known to those skilled in the art to afford compounds having an unsubstituted amino or carboxy substituent thereon.
Compounds of the invention where D is xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94 (where p is 2) may be prepared by methods disclosed above by reacting a compound of formula (E) with the sulfonyl chloride of the substituted thiophene or berizothiophene radical.
Compounds of the invention where E is xe2x80x94N(R5)xe2x80x94S(O)pxe2x80x94 (where p is 2), can be formed by reacting a substituted benzene sulfonyl chloride with a compound of formula (C) and then proceeding with Steps 3-5 above.
Compounds of formula (E) where R5a is hydrogen may be reacted with an appropriate alkylating agent prior to Step 4 to produce compounds where R5a is alkyl, aryl or aralkyl.
Compounds of the invention where R13 is xe2x80x94S(O)pxe2x80x94R8xe2x80x94N(R5)R6 (where p is 0) may be prepared from the corresponding halo as described herein. Compounds where R13 is heterocyclylalkyl may be made from substitution from the corresponding haloalkyl.
Compounds of formula (G) may be reacted with tertiary amines of the formula N(R9)(R16)2 where R9 and R16 are as described above in the Summary of the Invention for compounds of formula (I) by methods similar to those described above to prepare compounds of the invention wherein R14a is xe2x80x94N⊕(R9)(R16)2.
Any unoxidized sulfur and nitrogen may be oxidized after the final step in Reaction Scheme 1 by methods known to those skilled in the art to produce the desired oxidized substituents.
Compounds of formula (Ia) where R14a contains a xe2x80x94N(H)R10 group may be reacted with a heterocyclic compound having a reactive halogen to form compounds where R14a contains a xe2x80x94N(R10))R11 group wherein R11 is heterocyclyl.
Compounds of formula (Ia) where R14a contains a secondary amino substituent may be reacted with an aldehyde in an aprotic solvent, such as acetonitrile, in the presence of a reducing agent such as sodium cyanoborohydride to form compounds wherein the amino substituent is further substituted by an alkyl or aralkyl group.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R10 is hydrogen and R11 is xe2x80x94R8xe2x80x94OR5 (where R5 is hydrogen and R8 is ethyl or propyl optionally substituted by alkyl or alkoxyalkyl) can be reacted with cyanogen bromide to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R10 and R11 together with the nitrogen to which they are attached form optionally substituted 2-iminooxazolidin-3-yl or optionally substituted tetrahydro-2-amino-1,3-oxazinyl.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R11 is hydrogen and R10 is alkyl, aryl or aralkyl can be reacted with a cyano halide under basic conditions to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94CN, which can then be reacted with an azide in the presence of tributyl tin chloride in an aprotic solvent to form a compound of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R11 is tetrazolyl attached to the nitrogen through a carbon atom in the heterocyclic ring.
Compounds of formula (G) may be treated with an oxidizing agent to form the corresponding N-oxide when A is xe2x95x90Nxe2x80x94, and then treated with compounds of formula (H) to form other compounds of the invention where the pyridinyl ring is oxidized.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10))R11 where R10 is hydrogen and R11 is xe2x80x94R8xe2x80x94N(R5)R6 where R8 is ethyl or propyl and at least one R5 or R6 is hydrogen may be further treated with an ortho ester under mild acidic conditions to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10))R11 where R10 and R11 together with the nitrogen form an optionally substituted imidazolinyl. Other compounds of the invention may be similarly made. Such compounds wherein the imidazolinyl is substituted with an appropriate haloalkyl may be further treated with a compound of formula (H) in an aprotic solvent to form compounds wherein the imidazolinyl is substituted by the corresponding R14a group.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10))R11 where R10 and R11 together with the nitrogen form a 2-aminoimidazolyl in a protic solvent of the formula R5xe2x80x94OH may be further treated with a halogenating agent, such as N-chlorosuccinimide (NCS) in the presence of a strong acid to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10))R11 where R10 and R11 form a 2-iminoimidazolidinyl substituted at the 4- and 5-position with xe2x80x94OR5. Other compounds of the invention may be similarly made.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R10 is hydrogen and R11 is xe2x80x94R8xe2x80x94N(R5)R6 where either R5 or R6 is hydrogen may be further treated with phosphoryl chloride in the presence of a base, followed by treatment with a compound of the formula R5xe2x80x94OH to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R5)xe2x80x94P(O)(OR5)2.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R10 and R11 together with the nitrogen form 2-methylthioimidazolinyl may be further treated with N(R5)Hxe2x80x94R8xe2x80x94OR5 or with NH2xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6 to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10) R11 where R10 and R11 together with the nitrogen form a imidazolinyl substituted at the 2-position with xe2x80x94N(R5)xe2x80x94R8xe2x80x94OR5 or with xe2x95x90NR17 where R17 is xe2x80x94R8xe2x80x94C(O)xe2x80x94N(R5)R6, respectively.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R10 and R11 together with the nitrogen form a N-heterocyclic substituted with formyl may be treated under standard reducing conditions to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R10 and R11 together with the nitrogen form a N-heterocyclic substituted with hydroxymethyl. Other compounds of the invention may be similarly made.
Compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 where R10 is alkyl and R11 is oxazolin-2-yl may be treated with compounds of the formula R5xe2x80x94C(O)OH to form compounds of the invention where R14 is xe2x80x94N(R10)R11 where R10 is alkyl and R11 is xe2x80x94C(O)xe2x80x94N(R5)R15 where R5 is hydrogen and R15 is xe2x80x94R8xe2x80x94Oxe2x80x94C(O)R5 where R8 is ethyl.
Other compounds of formula (Ia) may be prepared according to the methods described herein according to methods known to those skilled in the art.
B. Preparation of Compounds of Formula (Ib)
Compounds of formula (Ib) are compounds of the invention and are prepared as follows in Reaction Scheme 2 wherein A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94, each R1a is as defined in Reaction Scheme 1 above; R2a is as defined in Reaction Scheme 1 above; R5 is as defined in the Summary of the Invention for compounds of formula (I); R5a is hydrogen; each R4 and R13 is as defined in the Summary of the Invention for compounds of formula (I), R14 is as described above in the Summary of the Invention for compounds of formula (I); and X is chloro or bromo: 
Compounds of formula (E) are prepared above in Reaction Scheme 1. Compounds of formula (J) are commercially available, e.g., from Lancaster, or may be prepared by methods known to those skilled in the art from compounds of formula (J) where X is xe2x80x94OCH3 (and where R13 or R14 do not contain a hydrolyzable group such as an ester), which is hydrolyzed to the acid and then converted to the acid chloride to form a compound of formula (J). In addition, compounds of formula (J) may be prepared according to methods disclosed herein.
In general, compounds of formula (Ib) are prepared by treating a compound of formula (E) with a compound of formula (J) in the presence of a base, preferably pyridine, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C. The reaction mixture is allowed to warm to ambient temperature and then stirred for about 8 to 20 hours, preferably for about 16 hours. The compound of formula (Ib) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and recrystallization.
Compounds of formula (Ib) where R14 is hydrogen, halo, formyl, acetyl, xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94C(O)OR5, xe2x80x94OR5, xe2x80x94S(O)pxe2x80x94R15 (where p is 0 to 2), xe2x80x94S(O)pxe2x80x94N(R5)R6, or xe2x80x94C(O)N(R5)R6; and R1a, R2a or R13 is alkyl, may be treated under standard halogenating conditions to form compounds where R1a, R2a or R13 is haloalkyl. The resulting compounds may then be treated with HN(R10)R11 or HN(R5)R6 to form compounds where R1a, R2a or R13 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 or xe2x80x94C(R7)Hxe2x80x94N(R5)R6.
Compounds of formula (Ib) where R14 is cyano may be treated with methanol or ethanol to form the corresponding imidate, which can then be treated with a compound of formula NH2xe2x80x94R8xe2x80x94N(R5)R6 where at least one R5 or R6 is hydrogen to form compounds of the invention where R14 is heterocyclyl containing at least two nitrogen atoms. Alternatively, the imidate so formed can be treated with a compound of formula N(H)(R5)R6 to form compounds of the invention where R14 is xe2x80x94C(NH)xe2x80x94N(R5)R6 which can be further treated under conditions similar to those described herein to form compounds of the invention where R14 is xe2x80x94C(NR17)xe2x80x94N(R5)R6 where R17 is as described above in the Summary of the Invention for compounds of formula (I).
Compounds of formula (Ib) where one or more R1a""s is hydroxy and R2 is hydrogen may be further treated with a compound of formula R5xe2x80x94C(O)xe2x80x94X where X is chloro or bromo to produce compounds of the invention where one or more R1a""s is xe2x80x94Oxe2x80x94C(O)xe2x80x94R5.
Compounds of formula (Ib) where R14 is xe2x80x94N(R10))R11 where at least one R10 or R11 is hydrogen can be treated with the appropriate Xxe2x80x94C(O)xe2x80x94R15 where X is bromo or chloro and R15 is as described above in the Summary of the Invention for compounds of formula (I) to form compounds of the invention where R14 is xe2x80x94N(R10)(R11) where R10 is hydrogen, alkyl, aryl or aralkyl and R11 is xe2x80x94C(O)xe2x80x94R15. During this process, other substitutents of compounds of formula (Ib) which contain a reactive hydroxy, amino or carboxy group may also be acylated.
C. Preparation of Compounds of Formula (Ic)
Compounds of formula (Ic) are compounds of the invention. They are prepared from compounds of formula (Ib) where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94, R14b is xe2x80x94CH2xe2x80x94R7 where R7 is hydrogen or alkyl as illustrated below in Reaction Scheme 3 wherein each R1a, R2a, R4, R5, R5a and R14a are as defined above in Reaction Scheme 1, and R13 is as defined above in the Summary of the Invention for compounds of formula (I), and X is bromo and chloro: 
Compounds of formula (Ib) are prepared herein. Compounds of formula (H) are commercially available or may be prepared according to methods known to those skilled in the art or by methods disclosed herein.
In general, compounds of formula (Ic) are prepared by first treating a compound of formula (Ib) in an organic solvent, such as benzene, with an halogenating agent under conditions to form the halide radical (such as irradiation). The compound of formula (K) is then isolated from the reaction mixture by standard techniques, such as concentration and trituration with solvent.
The compound of formula (K) in an aprotic solvent, such as methylene chloride, is treated with a compound of formula (H). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 18 hours. The compound of formula (Ic) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by HPLC.
Compounds of the invention where R13 is haloalkyl may be prepared by halogenating the corresponding alkyl substituent according to methods known to those skilled in the art. The compounds so formed can then be treated with the appropriate HN(R5)R6 group under conditions similar to those described above for preparing compounds of formula (Ic) to produce compounds of the invention where R13 is xe2x80x94C(R7)Hxe2x80x94N(R5)R6.
For better yield in the above Reaction Scheme, it is recommended that R1a, R2a, R4, and R13 do not contain an alkyl group, since this alkyl will also be halogenated and will subsequently react with compound of formula (H) during the reaction.
Compounds of formula (K) where X is bromo may be treated under standard substitution conditions to form compounds of formula (Ic) where R14a is hydroxy. These compounds may be further oxidized under standard oxidizing conditions to form compounds of the invention where R14 is formyl, which can further oxidized to form compounds of the invention where R14 is xe2x80x94C(O)OR5.
D. Preparation of Compounds of Formula (Id)
Compounds of formula (Id) are compounds of the invention where R13 is chloro. They are prepared from compounds of formula (M) which are compounds of either formula (G) or (K) as illustrated below in Reaction scheme 4 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94, each R1a, R2a, each R4, R5, R5a and R7 are as defined above in Reaction Scheme 1; R14c is xe2x80x94OR5, xe2x80x94Sxe2x80x94R15, xe2x80x94Sxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94Sxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Sxe2x80x94R8xe2x80x94OR5, xe2x80x94CN or xe2x80x94N(R10)R11 (where R10 and R11 together with the nitrogen to which they are attached form a a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, xe2x80x94R8xe2x80x94CN, xe2x95x90N(R17a), xe2x80x94OR5b, C(O)OR5b, xe2x80x94R8xe2x80x94C(O)OR5b, xe2x80x94N(R5b)R6b, xe2x80x94R8xe2x80x94N(R5b)R6b, xe2x80x94C(O)N(R5b)R6b, xe2x80x94R8xe2x80x94C(O)N(R5b)R6b, xe2x80x94N(R5b)xe2x80x94N(R5b)R6b, xe2x80x94C(O)R5b, xe2x80x94C(O)(R8xe2x80x94O)txe2x80x94R5b (where t is 1 to 6), xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94(R8xe2x80x94O)txe2x80x94R5b (where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5b, xe2x80x94C(O)OR5b, xe2x80x94N(R5)R6b, and xe2x80x94C(O)N(R5b)R6b) where R5b and R6b are alkyl, aryl or aralkyl and R17a is as defined for R17 in the Summary of the Invention for compounds of formula (I) except R17a can not be hydrogen; and where each R8, R9 and R15 are as defined above in the Summary of the Invention for compounds of formula (I); and Y is a metal cation: 
Compounds of formula (N) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, the compounds of formula (Id) are prepared by reacting a compound of formula (M) in an aprotic solvent with a compound of formula (N). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration of product, and flash chromatography.
Alternatively, a compound of formula HR14c in an aprotic solvent, such as DMF, is treated with a strong base, such as sodium hydride, at ambient temperature to form the corresponding salt. The compound of formula (M) in an aprotic solvent, such as DMF, is then added to the reaction mixture containing the salt. The reaction mixture is stirred at ambient temperature for about 10 to 20 hours, preferably for about 18 hours. The compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and flash chromatography.
In general, this reaction scheme is used for those amines, alcohols and mercapto compounds of formula HR14c which are not reactive enough to be used in Reaction Schemes 1 or 2 above. The salt can be formed in situ or can be isolated.
Compounds of formula (Ia) where R14c is cyano may be further treated with hydroxylamine under basic conditions in a protic solvent to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94C(NR17)xe2x80x94R10 where R17 is xe2x80x94OH.
E. Preparation of Compounds of Formula (If)
Compounds of formula (If) are compounds of the invention wherein a R14 substituent is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl, R10 is hydrogen, alkyl, aryl, aralkyl, xe2x80x94OR5 (where R5 is not hydrogen), xe2x80x94R8xe2x80x94OR5 (where R5 is not hydrogen), xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R5 can not be hydrogen), and heterocyclylalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R5 can not be hydrogen), and R11 is xe2x80x94S(O)2xe2x80x94R15a where R15a is alkyl, haloalkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94Oxe2x80x94C(O)xe2x80x94R5, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94R8xe2x80x94C(O)OR5, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5b, xe2x80x94R8xe2x80x94OR5b, xe2x80x94C(O)OR5b, xe2x80x94N(R5b)R6b and xe2x80x94C(O)N(R5b)R6b where each R5b and R6b is alkyl, aryl or aralkyl), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5b, xe2x80x94R8xe2x80x94OR5b, xe2x80x94C(O)OR5b, xe2x80x94N(R5b)R6b or xe2x80x94C(O)N(R5b)R6b where each R5b or R6b is alkyl, aryl or aralkyl). They are prepared from compounds of formula (M) as illustrated below in Reaction Scheme 5 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; Ra1a, R2a, R4, R5 and R5a are as described above in Reaction Scheme 1; R10 and R15a are as described above; and X is chloro or bromo: 
Compounds of formula (O) are commercially available or may be prepared according to methods known to those of ordinary skill in the art. The compound of formula (Ie) is a compound of formula (Ia) where R14a is xe2x80x94N(R10))R11 and is prepared herein.
In general, compounds of formula (If) are prepared by treating a compound of formula (Ie) in the presence of base, such as pyridine, at temperatures of between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at 0xc2x0 C., with a compound of formula (O). The reaction mixture is allowed to warm to ambient temperature and then stirred for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (If) is then isolated from the reaction mixture by standard isolation techniques, such as removal of solvents in vacuo and purification by flash chromatography.
This reaction scheme can also be used with compounds of the formula Xxe2x80x94S(O)2xe2x80x94N(R10))R11 to make compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94S(O)2xe2x80x94N(R10)R11.
F. Preparation of Compounds of Formula (Ig)
Compounds of formula (Ig) are compounds of the invention wherein a R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl, R10 is hydrogen, alkyl, aryl, aralkyl, xe2x80x94OR5 (where R5 is not hydrogen), xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6, cycloalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R5 can not be hydrogen), and heterocyclylalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R5 can not be hydrogen); and R11 is either xe2x80x94C(O)xe2x80x94N(R5)R15b or xe2x80x94C(S)xe2x80x94N(R5)R15b where each R5 is hydrogen and each R15b is hydrogen, alkyl, aryl, aralkyl, xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94C(O))OR5 or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6). They are prepared as described below in Reaction Scheme 6 wherein A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R2a, R4, R5, and R5a are as described above in Reaction Scheme 1; and R15b is as described above; and Z is either oxygen or sulfur: 
Compounds of formula (P) are commercially available, or may be prepared according to methods known to those skilled in the art. The compounds of formula (Ie) are compounds of formula (Ia) where R14a is xe2x80x94N(R10)R11 and are prepared by methods disclosed herein.
In general, compounds of formula (Ig) are prepared by treating a compound of formula (Ie) in an aprotic solvent, such as dioxane, with a compound of formula (P). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (Ig) is isolated from the reaction mixture by standard isolation techniques, such as concentration of product and purification by flash chromatography.
Alternatively, to produce compounds of formula (Ig) where R15b is hydrogen, compounds of formula (Ie) may be reacted with potassium isocyanate (Kxe2x80x94Nxe2x95x90Cxe2x95x90O). Alternatively, compounds of formula (Ie) may be reacted first with phosgene or equivalent, followed by reacting the resulting product with a disubstituted amine or a cyclic amine to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R10 is as described above for the compounds of formula (Ig) and R11 is xe2x80x94C(O)xe2x80x94N(R5)R15 where R5 and R15 are independently alkyl, aryl or aralkyl, or R5 and R15 together with the nitrogen to which they are attached form a N-heterocyclic ring as defined in the Summary of the Invention for compounds of formula (I).
Compounds of formula (Ig) where R15b is hydrogen can be further reacted with a halocetaldehyde dialkylacetal in the presence of a protic solvent, preferably an alkanol, to form compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl, and R10 is as described above for the Reaction Scheme and R11 is an oxazol-2-yl substituent.
G. Preparation of Compounds of Formula (Ih) and (Ij)
Compounds of formula (Ih) and (Ij) are compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl, R10 is hydrogen, alkyl, aryl or aralkyl, and R11 is xe2x80x94C(O)xe2x80x94R15 where R15 is xe2x80x94R8xe2x80x94OR5, xe2x80x94R8xe2x80x94N(R5)R6 or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6 (where R5 and R6 are as described above in the Summary of the Invention for compounds of formula (I))). These compounds are prepared as described below where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R2a, R4, R5, R5a are as described above in Reaction Scheme 1; and R7 and R8 are as described in the Summary of the Invention for compounds of formula (I); and R15c is xe2x80x94OR5, xe2x80x94N(R5)R6 or heterocyclyl (optonally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, xe2x80x94OR5, xe2x80x94C(O)OR5, xe2x80x94N(R5)R6 or xe2x80x94C(O)N(R5)R6 (where R5 and R6 are as described above in the Summary of the Invention for compounds of formula (I))), for example, 4-methylpiperidine; and each X is independently bromo or chloro: 
Compounds of formula (Q) and formula (R) are commercially available or may be prepared by methods known to those skilled in the art.
In general, the compounds of formula (Ij) are prepared by first treating a compound of formula (Ie) in an aprotic solvent, such as methylene chloride, in the presence of a base, such as diisopropylethylamine, at temperatures of between about xe2x88x9210xc2x0 C. and about 10xc2x0 C., preferably at about 0xc2x0 C., with a compound of formula (Q). The reaction mixture was allowed to warm to ambient temperature and stirred for about 4 to about 10 hours, preferably for about 7 hours. A compound of formula (R) is then added to the reaction mixture and the resulting reaction mixture is stirred about 10 to about 20 hours, preferably for about 16 hours. The compound of formula (Ij) is isolated from the reaction mixture by standard isolation techniques, such as concentration and purification by HPLC.
Alternatively, the compound of formula (Q) could be phosgene (Clxe2x80x94C(O)xe2x80x94Cl). Under these circumstances, the final product would have the R15c substituent directly attached to the carbonyl in the compound of formula (Ij). Alternatively, the compound of formula (Q) could also be Xxe2x80x94S(O)2xe2x80x94R8xe2x80x94X to produce compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R10 is as described above for compounds of formula (Ij) and R11 is xe2x80x94S(O)2xe2x80x94R15 where R15 is as described above for R15.
H. Preparation of Compounds of Formula (Ik)
Compounds of formula (Ik) are compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94N(R5)R6 where each R5 is as described in the Summary of the Invention for compounds of formula (I), where R6 and R7 are as described in the Summary of the Invention for compounds of formula (I), R10 is hydrogen, alkyl, aryl or aralkyl, and R17 is hydrogen, alkyl, aryl or aralkyl. They are prepared as illustrated below in Reaction Scheme 8 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R2a, R4, R5 and R5a are as described above in Reaction Scheme 1; R6 and R7 are as described in the Summary of the Invention for compounds of formula (I); R10 is hydrogen, alkyl, aryl or aralkyl; R17 is hydrogen, alkyl, aryl or aralkyl; and X is bromo or chloro, or X can also be other leaving groups such as alkylthio (methylthio) or pyrazolyl: 
Compounds of formula (S) are commercially available, or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Ik) are prepared by treating a compound of formula (Ie) in an aprotic solvent, such as DMF, in the presence of a base, such as triethylamine, with a compound of formula (S). The reaction mixture is stirred at ambient temperature to about 50xc2x0 C., preferably at about 45xc2x0 C., for about 2 to about 4 hours, preferably for about 3 hours. The reaction mixture is allowed to cool to ambient temperature and acidified, preferably with trifluoroacetic acid. The compound of formula (Ik) is isolated from the reaction mixture by standard isolation techniques, such as purification by HPLC.
I. Preparation of Compounds of Formula (Im)
Compounds of formula (Im) are compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)xe2x80x94C(NR17)xe2x80x94R10 where R7 is as described in the Summary of the Invention for compounds of formula (I) and each R10 and R17 are independently hydrogen, alkyl, aryl or aralkyl. They are prepared as illustrated below in Reaction Scheme 9 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R2a, R4, each R5 and R5a are as described above in Reaction Scheme 1; R7 is as described in the Summary of the Invention for compounds of formula (I); R10 and R17 are each independently hydrogen, alkyl, aryl or aralkyl; and R20 is alkyl: 
Compounds of formula (T) are commercially available or may be prepared according to methods known to those skilled in the art, or by methods descry herein. Compounds of formula (Ie) are prepared herein.
In general, compounds of formula (Im) are prepared by treating a compound of formula (Ie) in a protic solvent, such as methanol, with a compound of formula (T). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (Im) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and purification by HPLC.
J. Preparation of Compounds of Formula (In) and (Io)
Compounds of formula (In) are compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl, R10 is hydrogen, alkyl, aryl or aralkyl and R11 is xe2x80x94C(O)xe2x80x94N(R5)R15 or xe2x80x94C(S)xe2x80x94N(R5)R15; and compounds of formula (Io) are compounds of the invention where R14 is xe2x80x94C(R7)Hxe2x80x94N(R10)R11 where R7 is hydrogen or alkyl and R10 is hydrogen, alkyl, aryl or aralkyl, and R11 is heterocyclyl (optionally substituted by alkyl or oxo). They are prepared as illustrated below where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R2a, R4, each R5 and R5a are as described above in Reaction Scheme 1; R7 is as described in the Summary of the Invention for compounds of formula (I); R10 is hydrogen, alkyl, aryl or aralkyl; Z is oxygen or sulfur; n is 2 or 3; and X is bromo or chloro: 
Compounds of formula (U) are commercially available or may be prepared according to methods known to those skilled in the art. Compounds of Ia (Ie) are prepared herein.
In general, compounds of formula (Io) are prepared by first treating a compound of formula (Ie) in an aprotic solvent, such as tetrahydrofuran, at temperatures of about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably at about 0xc2x0 C., with an excess molar amount of a compound of formula (U). The reaction mixture is stirred at ambient temperature for about 4 to 10 hours, preferably for about 7 hours to form a compound of formula (In). The reaction mixture is cooled to a temperature of about xe2x88x9210xc2x0 C. to about 10xc2x0 C., preferably to about 0xc2x0 C., and a mild base, preferably triethylamine, is added to the reaction mixture. The resulting reaction mixture is then warmed to ambient temperature and stirred for about 20 to 30 hours, preferably for about 24 hours. The compound of formula (Io) is then isolated from the reaction mixture by standard isolation techniques, such as concentration of volatiles and purification by flash chromatography.
Other compounds of formula (U) may be used to produce compounds of formula (Io) wherein the heterocyclyl ring so formed is substituted by alkyl or by oxo. For example, if the nitrogen of the isocyanate is substituted by a branched alkyl with the terminal halo atom being 2 to 3 carbons away from the nitrogen, the compound so formed would have an alkyl substituent off the heterocyclic ring in the compound of formula (Io). Also, if the nitrogen is substituted by xe2x80x94C(O)xe2x80x94R where R17 is a haloalkyl (where the halo is on the terminal carbon of the haloalkyl group), one would end up with a heterocyclic ring with an oxo substituent next to the nitrogen atom of the heterocyclic.
K. Preparation of Compounds of Formula (Z)
Compounds of formula (Z) are intermediates in the preparation of the compounds of the invention and are prepared as illustrated below where R5a is alkyl, R7 is hydrogen or alkyl, R13a is hydrogen, halo, xe2x80x94OR5 (where R5 is alkyl, aryl or aralkyl); and R14a is as described above in Reaction Scheme 1; and each X is bromo or chloro: 
Compounds of formula (V) and formula (H) are commercially available or may be prepared according to methods known to those skilled in the art or methods disclosed herein.
In general, compounds of formula (Z) are prepared by first reacting a compound of formula (V) in an aprotic solvent, such as carbon tetrachloride, with a halogenating agent, such as sulfuryl chloride, in the presence of a catalytic agent, such as benzoyl peroxide. The reaction mixture is heated at reflux for about 12 to about 20 hours, preferably for about 17 hours, then cooled to ambient temperature. The compound of formula (W) is then isolated from the reaction mixture by standard isolation techniques, such as concentration of volatiles and purification by flash chromatography.
The compound of formula (W) in an aprotic solvent, such as methylene chloride, is then treated with a compound of formula (H). The resulting reaction mixture is then stirred at ambient temperature for about 10 to about 20 hours, preferably for about 16 hours. The compound of formula (X) is then isolated from the reaction mixture by standard isolation techniques, such as concentration of the product and purification by flash chromatography.
The compound of formula (X) in a protic solvent, such as ethanol, is then hydrolyzed under basic hydrolysis conditions (for example, by the addition of a strong base, such as sodium hydroxide) at ambient temperature. The compound of formula (Y) is then isolated from the reaction mixture by standard isolation techniques, such as concentration of volatiles, dissolution of product in water, acidification of the aqueous solution with a strong acid and filtration.
The compound of formula (Y) is then converted to a compound of formula (Z) by standard techniques.
Alternatively, the compound of formula (Y) can be isolated as the metal salt and then converted as is to a compound of formula (Z) by standard techniques.
Compounds of formula (Z) may be then be reacted with compounds of formula (E) to prepare compounds of the invention as described above in Reaction Scheme 1.
L. Preparation of Compounds of Formula (Iq)
Compounds of formula (Iq) are compounds of the invention wherein R2 is xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11 where R8 is as defined in the Summary of the Invention for compounds of formula (I) and R10 and R11 are as defined in the Summary of the Invention for compounds of formula (I) except that neither can be xe2x80x94OR5, xe2x80x94S(O)2xe2x80x94R15, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)xe2x80x94N(R5)R15 or xe2x80x94C(S)xe2x80x94N(R5)R15. They are prepared as illustrated below in Reaction Scheme 12 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R4 and R14 are as described in the Summary of the Invention for compounds of formula (I) except that none can be hydroxy, amino, carboxy or contain a nucleophilic amine; and R5 and R8 are as described in the Summary of the Invention for compounds of formula (I); and R2b is xe2x80x94N(R10)R11 where R10 and R11 are as defined above; and R13 is as described in the Summary of the Invention for compounds of formula (I) except that R13 can not be haloalkyl where the alkyl is substituted by only one halogen atom or R13 can not contain a nucleophilic nitrogen, and each X is bromo or chloro: 
Compounds of formula (AA) and (CC) are commercially available. Compounds of formula (Ip) are prepared by methods disclosed herein.
In general, compounds of formula (Iq) are prepared by treating a compound of formula (Ip) in an aprotic solvent, such as DMF, in the presence of a base, such as cesium carbonate, with a compound of formula (AA). The reaction mixture is stirred at ambient temperature for about 16 to about 20 hours to make the compound of formula (BB). A compound of formula (CC) is added to the reaction mixture and the resulting reaction mixture is heated to temperatures of between about 60xc2x0 C. and 70xc2x0 C., preferably to about 65xc2x0 C. The reaction mixture is maintained at that temperature for about 10 to about 14 hours, preferably for about 12 hours. The reaction mixture is then cooled to ambient temperature and the compound of formula (Iq) is isolated from the reaction mixture by standard isolation techniques, such as filtration and purification by HPLC.
When the compound of formula (CC) is a non-reactive amine, the anion of the amine may be prepared prior to reacting with the compound of formula (BB) to form the compound of formula (Iq). Such non-reactive amines include, but are not limited to, imidazole, tetrazole, and pyrazole.
M. Preparation of Compounds of Formula (Ir)
Compounds of formula (Ir) are compounds of the invention wherein R2 is xe2x80x94Oxe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94OR9, xe2x80x94Oxe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94Oxe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94Oxe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Oxe2x80x94C(O)xe2x80x94R5 where each R5, R9 and R8 are as defined above in the Summary of the Invention for compounds of formula (I); and R10 and R11 are as defined above in the Summary of the Invention for compounds of formula (I). They are prepared as illustrated below in Reaction Scheme 13 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R4 and R14 are as described in the Summary of the Invention for compounds of formula (I) except that none can be hydroxy, amino, carboxy or contain a nucleophilic amine; and R5 and R8 are as defined in the Summary of the Invention for compounds of formula (I), and R13 is as described in the Summary of the Invention for compounds of formula (I) except that R13 can not be haloalkyl where the alkyl is substituted by only one halogen atom or R13 can not contain a nucleophilic nitrogen, and R2c is xe2x80x94R8xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94R5, xe2x80x94(R8xe2x80x94O)txe2x80x94R5 (where t is 1 to 6), xe2x80x94R8xe2x80x94C(O)OR5, xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94C(O)xe2x80x94R9 where each R5, R8, R9, R10 and R11 are as defined above; and X is chloro or bromo: 
Compounds of formula (DD) are commercially available or may be prepared according to methods known to those of ordinary skill in the art. Compounds of formula (Ip) are prepared herein.
In general, compounds of formula (Ir) are prepared by treating a compound of formula (Ip) in an aprotic solvent, such as DMF, in the presence of a strong base, such as sodium hydride, at ambient temperature with a compound of formula (DD). The reaction mixture is stirred for about 1 hour to about 4 hours, preferably for about 3 hours, and then cooled to temperatures of between about xe2x88x9210xc2x0 C. and 10xc2x0 C., preferably to 0xc2x0 C. The reaction mixture is then acidified with a mild acid, such as trifluoroacetic acid. The compound of formula (Ir) is then isolated from the reaction mixture by standard isolation techniques, such as purification by HPLC.
Alternatively, compounds of formula (Ir) may be prepared by treating a compound of formula (Ip) in an aprotic solvent, such as DMF, in the presence of a strong base, such as cesium carbonate, at ambient temperature with a compound of formula (DD). The reaction mixture is then heated to between about 50xc2x0 C. and about 65xc2x0 C., preferably to about 60xc2x0 C. and stirred at that temperature for about 10 to about 20 hours, preferably for about 16 hours. The reaction mixture is then allowed to cool to ambient temperature and filtered. The resulting filtrate is then acidified by a mild acid, such as trifluoroacetic acid, and the compound of formula (Ir) is isolated from the reaction mixture by standard isolation techniques, such as purification by HPLC.
N. Preparation of Compounds of Formula (Is)
Compounds of formula (Is) are compounds of the invention wherein R2 is xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(R10)R11 where R10 and R11 are as defined above in the Summary of the Invention for compounds of formula (I) except that neither can be xe2x80x94OR5, xe2x80x94S(O)2xe2x80x94R15, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)xe2x80x94N(R5)R15 or xe2x80x94C(S)xe2x80x94N(R5)R15. They are prepared as illustrated below in Reaction Scheme 14 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R4 and R14 are as described in the Summary of the Invention for compounds of formula (I) except that none can be hydroxy, amino, carboxy or contain a nucleophilic amine; and R5 and R8 are as described in the Summary of the Invention for compounds of formula (I); and R2b is xe2x80x94N(R10)R11 where R10 and R11 are as defined above; and R13 is as described in the Summary of the Invention for compounds of formula (I) except that R13 can not be haloalkyl where the alkyl is substituted by only one halogen atom or R13 can not contain a nucleophilic nitrogen; and each X is bromo or chloro: 
Compounds of formula (EE) and (CC) are commercially available or may be prepared according to methods known to those skilled in the art. Compounds of formula (Ip) are prepared herein.
In general, compounds of formula (Is) are prepared by first treating a compound of formula (Ip) in an aprotic solvent, such as DMF, with a compound of formula (EE) in the presence of strong base, such as cesium carbonate. The reaction mixture is stirred at ambient temperature for about 3 days. The compound of formula (FF) is then isolated from the reaction mixture by standard isolation techniques such as filtration and concentration.
The compound of formula (FF) in an aprotic solvent, preferably DMF, is then treated with salt of a compound of formula (CC). The reaction mixture is stirred at ambient temperature for about 16 to about 20 hours, preferably for about 18 hours. The compound of formula (Is) is then isolated from the reaction mixture by standard isolation techniques, such as concentration of volatiles and purification by HPLC.
O. Preparation of Compounds of Formula (It)
Compounds of formula (It) are compounds of the invention wherein R2 is xe2x80x94Oxe2x80x94R8xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94OR5 where R5 and R8 are as defined in the Summary of the Invention for compounds of formula (I). They are prepared as illustrated in the following Reaction Scheme 15 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a, R4 and R14 are as described in the Summary of the Invention for compounds of formula (I) except that none can be hydroxy, amino, carboxy or contain a nucleophilic amine; and R5, and R8 are as described in the Summary of the Invention for compounds of formula (I); and R13 is as described in the Summary of the Invention for compounds of formula (I) except that R13 can not be haloalkyl where the alkyl is substituted by only one halogen atom or R13 can not contain a nucleophilic nitrogen; and each X is bromo or chloro: 
Compounds of formula (FF) are prepared herein. Compounds of formula (HH) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (It) are prepared by treating a compound of formula (FF) in an aprotic solvent, such as methylene chloride, with an excess amount of a compound of formula (HH) in the presence of an oxidant, such as dichlorodicyanobenzoquinone. The reaction mixture is stirred at ambient temperature for about 24 to about 48 hours, preferably for about 48 hours. The reaction is then quenched with the addition of a mild base, such as aqueous sodium bicarbonate. The compound of formula (It) is isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration of volatiles and purification by flash chromatography.
P. Preparation of Compounds of Formula (Iv)
Compounds of formula (Iv) are compounds of the invention wherein the R2 substituent is in the 4-position and is xe2x80x94Sxe2x80x94R9, xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Sxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Sxe2x80x94R8xe2x80x94C(O)OR5, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5 (where R5, R6, R8, R9 and R12 are as defined in the Summary of the Invention for compounds of formula (I) and R10 and R11 are as defined in the Summary of the Invention for compounds of formula (I) except that neither can be xe2x80x94OR5, xe2x80x94S(O)2xe2x80x94R15, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)N(R5)R15 or xe2x80x94C(S)xe2x80x94N(R5)R15 when R2 is xe2x80x94N(R10)R11). They are prepared as illustrated below in Reaction Scheme 16 wherein R1a is halo; and R4 and R14 are as described in the Summary of the Invention for compounds of formula (I) except that neither can contain a nucleophilic amine; and R5 is as described in the Summary of the Invention for compounds of formula (I); and R13 is as described in the Summary of the Invention for compounds of formula (I) except that R13 can not be haloalkyl where the alkyl is substituted by only one halogen atom or R13 can not contain a nucleophilic nitrogen; and R2d is xe2x80x94Sxe2x80x94R9, xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94Sxe2x80x94R8xe2x80x94N(R5)R6, xe2x80x94Sxe2x80x94R8xe2x80x94C(O)OR5, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5 (where R5, R6, R8, R9, R10, R11 and R12 are as defined above for R2): 
Compounds of formula (II) are commercially available, or may be prepared according to methods known to those skilled in the art. Compounds of formula (Iu) may be prepared according to methods disclosed herein.
In general, compounds of formula (Iv) are prepared by treating a compound of formula (Iu) with a compound of formula (II) in the presence of a base. The reaction mixture is heated to temperatures of between about 80xc2x0 C. and about 105xc2x0 C., preferably at about 85xc2x0 C., for about 10 to about 20 hours, preferably for about 15 hours. The compound of formula (Iv) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and purification by HPLC.
Q. Preparation of Compounds of Formula (Ip)
Compounds of formula (Ip) are compounds of the invention wherein R2 is hydroxy. These compounds are prepared as illustrated below where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; and R1, R4, R5, R13, R14, m and n are as defined above in the Summary of the Invention for compounds of formula (I): 
Compounds of formula (Iw) are compounds of the invention which are prepared by the methods disclosed herein.
In general, compounds of formula (Ip) are prepared by treating a compound of formula (Iw) in an aprotic solvent, such as methylene chloride, with boron tribromide at ambient temperature. The reaction mixture is stirred for about 10 to about 20 hours, preferably for about 18 hours. The compound of formula (Ip) is then isolated from the reaction mixture by standard isolation techniques, such as extraction and concentration.
During this reaction, if any of the other substituents, such as R1, R4, etc., contain an ester group or a lower alkyl ether group, the ester group will also be hydrolyzed to the corresponding acid and the ether group will be hydrolyzed to the corresponding alcohol.
R. Preparation of Compounds of Formula (Eb)
Compounds of formula (Eb) are compounds of formula (E) wherein R1a is in the 5-position and is halo. These compounds, which are intermediates in the preparation of the compounds of the invention, may be prepared as illustrated below in Reaction Scheme 18 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R2, R4, and R5 are as described above in the Summary of the Invention for compounds of formula (I); and R5a is hydrogen, and X is chloro or bromo: 
Compounds of formula (Ea) are prepared by methods disclosed herein.
In general, compounds of formula (Eb) are prepared by treating a compound of Ea in an organic solvent, such as benzene, with a halogenating agent. The reaction mixture is heated to temperatures of about 45xc2x0 C. to about 55xc2x0 C., preferably to about 50xc2x0 C. to about 55xc2x0 C. The reaction mixture is allowed to cool to ambient temperature and the compound of formula (Eb) is then isolated from the reaction mixture by standard isolation techniques, such as concentration, extraction and recrystallization.
S. Preparation of Compounds of Formula (Db)
Compounds of formula (Db) are compounds of formula (D) where the R1a substituent is in the 5-position and is chloro and R2 is in the 3-position and is xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5 (where R5, R8, R10, R11 and R12 are as defined in the Summary of the Invention for compounds of formula (I) except that R10 and R11 can not be xe2x80x94S(O)2xe2x80x94R15, xe2x80x94C(O)xe2x80x94R15, xe2x80x94C(O)N(R5)R15 or xe2x80x94C(S)N(R5)R15 when R2 is xe2x80x94N(R10)R11). These compounds, which are intermediates in the preparation of the compounds of the invention, are prepared as illustrated below in Reaction Scheme 19 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R4 and R5 are as described in the Summary of the Invention for compounds of formula (I); and R2e is xe2x80x94N(R10)R11, xe2x80x94N(R5)xe2x80x94R8xe2x80x94N(R10)R11, or xe2x80x94N(R5)xe2x80x94CH(R12)xe2x80x94C(O)OR5 (where R5, R8, R10, R11, and R12 are as defined above for R2): 
Compounds of formula (Da) are prepared by methods described herein. Compound of formula (JJ) are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Db) are prepared by treating a compound of formula (Da) in a polar aprotic solvent, such as DMSO, with a compound of formula (JJ) in the presence of a base, such as diisopropylethylamine. The reaction mixture is heated to temperatures of between about 100xc2x0 C. to about 120xc2x0 C., preferably to about 110xc2x0 C. to about 120xc2x0 C. and maintained at that temperature for about 3 to about 5 hours, preferably for about 4 hours. The reaction mixture is then cooled to ambient temperature and the compound of formula (Db) is isolated from the reaction mixture by standard isolation techniques such as extraction, concentration and purification by flash chromatography.
T. Preparation of Compounds of Formula (Ec)
Compounds of formula (Ec) are compounds of formula (E) where R5a is hydrogen. These compounds, which are intermediates in the preparation of the compounds of the invention, may be prepared as illustrated below in Reaction Scheme 20 where A is xe2x95x90CHxe2x80x94 or xe2x95x90Nxe2x80x94; R1a is hydrogen, alkyl, aryl, aralkyl, halo, cyano, xe2x80x94OR, xe2x80x94S(O)pxe2x80x94R9 (where p is 0 to 2), xe2x80x94C(O)OR5, xe2x80x94C(O)xe2x80x94N(R5)R6 and xe2x80x94N(R5)R6 (where each R5 and R6 can not be hydrogen and R9 is alkyl, aryl, or aralkyl); and R2a is as defined above in Reaction Scheme 1, and R4 and R5 are as defined above in the Summary of the Invention for compounds of formula (I): 
Compounds of formula (KK) and formula (C) and phosgene are commercially available or may be prepared according to methods known to those skilled in the art.
In general, compounds of formula (Ec) are prepared by first treating a compound of formual (KK) with phosgene in an aprotic solvent, such as dioxane. The reaction mixture is stirred at ambient temperature to about 70xc2x0 C., preferably at about 65xc2x0 C., for about 8 to about 12 hours, preferably for about 10 hours. The reaction mixture is cooled to ambient temperature and the compound of formula (LL) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and evaporation of solvents.
The compound of formula (LL) in a polar aprotic solvent, such as dioxane, is treated with a compound of formula (C). The reaction mixture is heated at reflux for about 10 to about 20 hours, preferably for about 15 hour;. The reaction mixture is allowed to cool to ambient temperature and the compound of formula (Ec) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and concentration.
U. Preparation of Compounds of Formula (F)
Compounds of formula (F) are intermediates used to prepare compounds of the invention and may be prepared as illustrated below in Reaction Scheme 21 wherein each R5 is alkyl, R7 is hydrogen or alkyl; and M is a metal cation and X is bromo or chloro: 
Compounds of formula (MM) are commercially available or may be prepared according to methods disclosed herein or by standard methods known to those of ordinary skill in the art.
In general, compounds of formula (F) are prepared by first treating a compound of formula (MM) in a similar mariner as that described herein for the preparation of compounds of formula (W) to prepare a compound of formula (NN).
The compound of formula (NN) in a mild acidic aqueous solution is then treated with a compound of formula (SS). The reaction mixture is heated to reflux for about 20 hours to about 30 hours, preferably for about 24 hours. The reaction mixture is then cooled to ambient temperature and the compound of formula (OO) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and extraction.
The compound of formula (OO) is then hydrolyzed under standard basic conditions to produce the compound of formula (PP). The compound of formula (PP) may be isolated as the metal salt and may be used as such in the next step.
The compound of formula (PP) is then converted to the acid halide by treatment with the appropriate agent, such as thionyl chloride or thionyl bromide. The resulting compound of formula (F) is isolated from the reaction mixture by standard isolation techniques.
V. Preparation of the Compound of Formula (RR)
The compound of formula (RR) is an intermediate in the preparation of compounds of the invention and is prepared as illustrated below in Reaction Scheme 22: 
The compound of formula (QQ) is commercially available.
In general, the compound of formula (RR) is prepared by treating the compound of formula (QQ) in the presence of a mild acid, such as trifluoroacetic acid, with nitric acid. The reaction mixture is stirred at temperatures of between about xe2x88x9210xc2x0 C. and 10xc2x0 C., preferably at about 0xc2x0 C., for about 30 minutes to an hour, preferably for about 1 hour. The reaction mixture is warmed to ambient temperature and stirred for about 2 to about 4 hours, preferably for about 3 hours. The compound of formula (RR) is then isolated from the reaction mixture by standard isolation techniques, such as precipitation and filtration.
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques.